Preprint A Proposed Mechanism for ME/CFS Invoking Macrophage Fc-gamma-RI and Interferon Gamma, 2025, Edwards, Cambridge and Cliff

[hotblack]

Audio versions are available here
https://u.pcloud.link/publink/show?code=kZLPeS5ZBEzVhhjXk8hM18y29vgEGVG6zSvk

Any questions, comments or feedback please use this separate thread so we don’t distract from discussion of the paper. Thanks.

 

[Jonathan Edwards]

I am interested in to what extent dealing with the immune processes would address the proposed nervous system involvement. Would you think the plasticity/hypervigilance would reverse course if a suitable immune treatment was found?

A very important question. My hope is that the whole thing could be reversed from the immune end - whatever the chain of events is. Maybe doing that early would be important but maybe not. My guess is that reversal even late on is doable but may take a lot of work to find a way to do it.

In what sense is the hypervigilance state tied to the autonomic control mechanisms? If the sickness response developed to promote convalescence, what is the advantage of actually ramping up the autonomic nervous system instead of just making the subject feel bad? It is difficult for me to square my experience of hyperactive sympathetic nervous system states prior to getting sick, to my current experience with "dysautonomia" (but perhaps they are different hyperactive mechanisms).

I don't think we need to look for 'advantage'. If a servo system goes haywire it may produce effects way beyond what is useful. If the fridge thermostat goes dodgy you may find all your milk and lettuce frozen.

 

[Jonathan Edwards]

So, perhaps there are T-cell clones in tissues, rather than blood.

That is an issue, perhaps, but mature T cells have a circulatory systemic policing function so they should turn up in blood.

I am interested in the discussion of MS - is T cell clonality recognised? There is a huge amount of guff about T cell responses in MS. It seems it didn't show up in that study?

 

[V.R.T.]

A very important question. My hope is that the whole thing could be reversed from the immune end - whatever the chain of events is. Maybe doing that early would be important but maybe not. My guess is that reversal even late on is doable but may take a lot of work to find a way to do it.

To be clear, are you talking about early and late in terms of the time course of the disease or in terms of the chain of causality i.e. early being closer to the upstream mechanisms that cause it?

Oh and would this reversal be necessary for an effective treatment or just for a cure that turns off disease memory and therefore prevents recurrance?

 

[Trish]

There are people who meet ME/CFS diagnostic guidelines at 4 months after an acute disease, 6 months, even a year or so who go on to recover. We have evidence that suggests this is common, even in adults. Suggesting otherwise helps build up these people who recover from a relatively short term illness (at least 'short' relative to life-long ME/CFS) as special. Hence we get Garner and other evangelical sellers of various forms of pseudoscience claiming to have special knowledge. I'd really like to see an 'established' qualifier in there, e.g. 'established adult-onset illness, that is ME/CFS that has been present for more than three years, seems rarely to fully resolve'.

I think this is covered by this section:

Relation to Intracellular Infection
It is widely accepted that ME/CFS onset frequently follows infection with an intracellular pathogen, including viruses such as Epstein-Barr and the atypical bacterium Coxiella burnetii[31]. However, the role of immediately antecedent infection may be one of a non-specific and inconsistent trigger. Relatively short-term post-viral fatigue, lasting a matter of months, is also common for a number of infections, notably EBV, and diagnostic boundaries are uncertain. There is no clear time relation between infective illness and onset of ME/CFS, which may be immediate or delayed for weeks or months in patient reports. Furthermore, the symptoms of ME/CFS overlap with those of viral infection.

 

[Jonathan Edwards]

So how does one go about looking for macrophages in ME/CFS tissue to see (1) if FcγRI is up regulated? (2) Does T-lymphocyte co-location cause the FcγRI up regulation for example. Where do we look? What type of tissue would be needed.

My guess is that sampling problems for solid tissues are so huge that nobody will ever be able to use them effectively. We came to that conclusion with tissue samples in RA in the 1990s. My current favourite is looking at short term co-cultures of T cell subsets from blood with macrophages that can be pre-primed in vitro using ELISpot type techniques. But the lesson from RA was that you can infer what you think is going on and prove you have identified the right players with a drug therapy without ever actually observing the predicted events in tissues.

 

[Jonathan Edwards]

Would your model still hold if a significant number of patients had low IFN-γ levels in blood, @Jonathan Edwards? Or asked differently, would it hold in patients with low IFN-γ?

I doubt that will be a problem but if gamma interferon is being used locally by transient T cell passage through tissues then blood levels may be normal and even conceivably low if there is a regulatory increase in circulating TGF beta, which some studies have suggested.

 

[Jonathan Edwards]

I would like to present this paper to my facebook groups. I am thinking if this work is somehow unique and revolutioning. Can we say that it's unique or how to describe it in the best way?

Charles Shepherd asked if I had a lay summary. I think that is quite tricky. The paper is really an attempt to lay out a framework for testing theories based on data that may be coming through from immunology studies, proteomics and genetics - with a best shot at a suggestion for now. It is not intended as a 'breakthrough idea' so much as a way of saying ' we may now, or very soon, be in a position to start working out what is really wrong, so let's see what we need to explain'.

 

[Jonathan Edwards]

“FcγRI” I’m going for “Fc gamma R one”
“α1β4 integrin traffic domain”, “Alpha one beta four integrin traffic domain”?
“MAIT cells are pronounced “mate” aren’t they?

correct

 

[Trish]

Quotes from the article:

The evidence for long-term epigenetic or ‘learnt’ neuroplastic change in ME/CFS remains at present inconclusive, but it is possible that it could contribute to the difference between the common resolving ‘post-viral fatigue syndrome’ seen after infections like EBV and the persistent disabling illness of ME/CFS, perhaps because of genetic susceptibility. This might also be relevant to the finding that cytokine and lymphocyte population shifts in ME/CFS appear to be more pronounced in the first 3-5 years after onset compared to the longer-term situation[56][5].

The synthesis below suggests that ME/CFS is one of a range of ‘immune hypervigilance’ states. In this context, we cannot rule out the possibility that the higher rate of diagnosis of ME/CFS in women is in part due to a greater ‘health vigilance’ in women – of central nervous origin.
_____________________

I would like to understand these better. I worry that they may be misused by the brain retraining advocates.

 

[butter.]

This paper is interesting also in the sense that it is a recommendation/invitation to pharma scouts to at very least sponsor some daratumumab. It's much easier for pharma to do this with a paper like this one out.

 

[Jonathan Edwards]

I would like to understand these better. I worry that they may be misused by the brain retraining advocates.

So would I.

I think the worry is justified but I think the playing field has to be kept seriously level, and not least to make it plain that nobody is intending to tilt it.

If the female nervous system is more susceptible to certain immune signals then we need to know that. Women are better at sensing odours it is claimed. Some women can see more colours than any man. Diagnostic rates may be skewed by sensible vigilance. We cannot rule out such possibilities if we want to find the right answer.

 

[Nightsong]

Thanks for all the comments. There are already one or two I (we) will respond to with an updated text. Nobody so far has noticed there is one study cited that has no reference and one reference with no citation!

Haven't reviewed them in detail but, at a quick glance, there seem to be a few other errors in the references - some examples under the tag.

Spoiler: References...

This one seems wrong - can't be thousands of pages:

Edwards JC, Cambridge G, Abrahams VM (1999). "Do self-perpetuating B lymphocytes drive human autoimmune disease?" Immunology 97:1868–96

and this one (should be Peterson):

Carruthers BM, Jain AK, De Meirleir KL, Peterso DL

and this one (should be MedRxiv):

Beentjes SV, Kaczmarczyk J, Cassar A, Samm GL, Hejazi NS, Khamseh A, Ponting CP (2024). "Replicated blood-based biomarkers for Myalgic Encephalomyelitis not explicable by inactivity." MedRchiv. ...

and this one (should be "Accelerated"):

Lord JM, Veenith T, Sullivan J, Sharma-Oates A, Richter AG, Greening NJ et al. (2024). "Accelarated immune ageing is associated with COVID-19 disease severity." ...

and this one (should be "Taylor"):

Conrad N, Misra S, Verbakel Y, Molenberghs G, Taylore PN, et al. (2023). "Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK." The Lancet 401:10391:1878–1890.

What potentially confirmatory experimental approaches would you envisage being of most use - flow cytometry, scRNA-seq, ELISPOT, CITE-seq?

Tsuda et al (link) on IFN-γ receptor signalling in spinal microglia & its role in allodynia in a murine model may be of some additional interest.

I'm sure I'll have some more salient comments as & when I'm able to read through in detail but thanks for all your work on this; it's an extremely interesting hypothesis.

 

[Trish]

I find this part of interest for possible future research. Is there an obvious way people can be investigated during a bout of flu, for example by visiting them to take blood samples?

Quote:
ME/CFS highlights the fact that we still do not know that much about the mechanism of the ‘malaise’ of acute infection, mimicked by symptoms in ME/CFS. What signals generate myalgia, and where are they produced? Although evidence for shifts in energy metabolism pathways has accumulated, this is unlikely to be directly responsible for reduced muscle power through the unavailability of energy-dependent pathways[42]. It may, nevertheless, via associated inhibitory sensory signals, make an important contribution to disability.

 

[Jonathan Edwards]

I find this part of interest for possible future research. Is there an obvious way people can be investigated during a bout of flu, for example by visiting them to take blood samples?

I think the same co-culture ELISpot type studies I suggest for ME/CFS might prove useful. The problem with acute infection though is that there may be lots of signals occurring and it may be more difficult to work out which is doing what.

 

[Trish]

Would it be possible for someone to draw a flow diagram of the stages in the proposed pathway? Starting perhaps with genetic predisposition (to what?), then adding a trigger, leading to a series of biological steps and ending with symptoms?
____________________

Probably not something to go into in detail on this thread, but I'd be interested in how this particular hypothesis might or might not explain some other observations that I think are not mentioned, for example:

'something in the blood' that people were getting excited about 5 years or more ago: Blog: 'Summary so far of "Something in the blood"' by Simon McGrath

Prusty's fibronectin observation

NK cell findings

 

[Sean]

I appreciate the subtleties here but my statement was designed to make a simple point - that ME/CFS is not congenital.

Point taken.

My interest in this is that if a prodromal phase exists and can be identified, that opens the possibility of intervening much earlier, with better management if nothing else for now, to prevent it expanding into the full blown state, or reduce the consequences if it does. At least for some patients.

And if there is a conversion from prodromal phase we need another event - which is what the paragraph is about.

I agree. Any explanation involving a prodromal phase needs to cover why there is a major shift in disease status over a short (or relatively short) period of time – the expansion event or phase.

RA after pregnancy quite often resolves for good after a period of months.

Interesting, given some mothers report something similar in ME/CFS during pregnancy and for some time after.

 

[Sean]

Thank you to the authors for caring enough to put this together.

 

[OrganicChilli]

In particular the possibility that there might be a long pro-dromal phase for many, and that some may never progress beyond that phase while still experiencing a subtle and unrecognised but still practically significant reduction in health status.

I had that for a few years and it's the reason why I don't know if my onset was caused by covid or the vaccine. Even when my symptoms started getting really bad, it took me a few months to realise that I hadn't become I'll out of the blue, but had been symptomatic for a while. It wasn't a significant reduction in my health status though. It was so insignificant, I thought everyone was like that and it was a sign of getting older. In hindsight I think it was the first sign of cognitive exhaustion.

It may be that the cognitive component of ME/CFS and its consequences are dominate during a pro-dromal phase, which would skew interpretation from the start, including not even realising there is any health problem at all. Then, if it later becomes the full blown expression of the syndrome, the physical component comes more to the fore.

Ah this summarises my experience really well. I had to take a nap every day after work even though I was working remotely, but I could walk 10k steps every day or even 25k steps on holiday without issues.

 

[Jonathan Edwards]

Would it be possible for someone to draw a flow diagram of the stages in the proposed pathway? Starting perhaps with genetic predisposition (to what?), then adding a trigger, leading to a series of biological steps and ending with symptoms?
____________________

Probably not something to go into in detail on this thread, but I'd be interested in how this particular hypothesis might or might not explain some other observations that I think are not mentioned, for example:

'something in the blood' that people were getting excited about 5 years or more ago: Blog: 'Summary so far of "Something in the blood"' by Simon McGrath

Prusty's fibronectin observation

NK cell findings

Jackie Cliff volunteered to do a diagram and then realised how tricky it would be. In my experience diagrams are mostly too vague to be helpful unless the whole mechanism is sorted out. We managed to do it for RA when we had things clear but this is not at that stage by any means.

The something in the blood I think came from the original nano needle studies that suggested an active ingredient in ME/CFS serum. Those studies never got replicated and always seemed pretty hard to interpret. Our hypothesis involves antibody populations in blood being involved, and they might conceivably be seen in that light but I don't think the original data were firm enough to revisit.

The finding of low NK numbers and function would fit with a compensatory rise in TGF beta and GDF15, as mentioned in the paper. But again, nobody is very certain how reproducible these findings ever were.

Not sure about Prusty. I don't remember that.
Edit: I wouldn't get too excited about fibronectin in serum. Serum is plasma after it has clotted and all sorts of changes to proteins like fibronectin could occur with samples after leaving the patient.